An interdisciplinary team of University of Pennsylvania researchers in Medicine and Engineering has been awarded multiple federal nanotechnology grants, one from the National Science Foundation (NSF) and two from the National Institutes of Health (NIH), interfacing computer modeling with laboratory experiments to design nanocarriers for targeted drug delivery. The grants total over $5 million in research funding.

Nanocarriers are tiny, engineered particles that are able to contain small drug molecules in their hollow interiors and can be directed to specific diseased tissues by the addition of targeting molecules bound to their exteriors. Nanocarriers injected into the bloodstream circulate to the site of disease, where the targeting molecules bind to receptors on the surface of diseased cells so that they are taken up out of the blood and into the disease tissue. This is followed by release of the drug as a site-specific therapy. The choice of targeting molecule, the means by which it is tethered to the nanocarrier, the chemical makeup of the nanocarrier itself and the transport characteristics of the drug being offloaded from the nanocarrier are all design elements critical to the efficiency with which the payload of medicine is delivered to diseased cells while healthy cells are ignored. This is a multidisciplinary bioengineering problem that requires study by coupling computational methodology with laboratory experimental techniques.

The research leadership core is headed by David Eckmann, professor of anesthesiology and critical care in Penn’s Perelman School of Medicine and professor of bioengineering in Penn’s School of Engineering & Applied Science (SEAS); Ravi Radhakrishnan, associate professor in the departments of bioengineering and chemical and biomolecular engineering in SEAS and PortonovoAyyaswamy, professor in the department of mechanical engineering and applied mechanics in SEAS. The research team also includes Russell Composto, and Andrew Tsourkas of SEAS as well as Vladimir Muzykantov of Medicine.

The core investigators led by Dr. Radhakrishnan were awarded a new $407,000, three-year research grant by NSF for the development of computer models that will be instrumental in improving targeted nanocarrier design by focusing on the physical environment for binding interactions leading to nanocarrier arrest on the target cell. The specific cell surface behaviors the investigators are addressing include receptor diffusion on the cell membrane and membrane undulations involved in engulfing and internalizing the nanocarriers into the cell interior.

As a complement to this work, the core group including professors Muzykantov and Composto received a $1.97 million, four-year competing renewal R01 grant from the NIH’s National Institute of Biomedical Imaging and Bioengineering to model the hydrodynamic and microscopic interactions mediating nanocarrier motion during targeted drug delivery and to model transport and controlled drug release from nanocarriers in blood flow as well as to study nanocarrier targeting kinetics, internalization and intracellular drug delivery experimentally.

To add to their portfolio, the core group along with Drs. Muzykantov and Tsourkas received notification that a $2.7 million, five-year U01 grant from the NIH’s National Institute of Biomedical Imaging and Bioengineering has been funded. This grant focuses on the development of new computational methods to bridge the multiple different time and length scales that are inherently present and required to integrate molecular models of binding interactions with the hydrodynamic interactions at play. The experimental component of this effort involves specific chemistry to optimize the tethering of targeting molecules on the nanocarrier surface to enhance binding for efficient drug delivery.

Ultimately these grant funds should enable this multidisciplinary research team to make large strides in the development and validation of computational techniques required to design and optimize endothelial-targeted, nanocarrier-based drug delivery.